The ability to detect mechanical stimuli is an essential and prevalent characteristic of living organisms, and is found from bacteria to simple metazoans to the most complex of mammals. Indeed, the ability to detect mechanical stimuli and convert them into electrical signals forms the basis of many central aspects of animal life, such as light touch, heavy touch, proprioception, baroreception, balance, and the crown jewel, hearing. Even the ability of cells to stop growing when in contact with neighboring cells is likely dependent on mechanical stimuli. Not surprisingly, therefore, numerous human conditions result at least in part from an inability to detect mechanical stimuli, such as Meniere's Disease, sensorineural deafness, blood pressure disorders, and various types of cancers.
In general, the variety of known mechanosensory modalities are thought to be mediated by mechanically-gated cation channels present within the membrane of receptor cells. This view has come in large part from detailed studies into the physiology of mechanosensation using various cell types involved in mechanosensory detection, such as the hair cells of the vertebrate inner ear, single-celled ciliates such as Paramecium, or the sensory neurons of Drosophila (see, e.g., Kernan et al., Neuron 12:1195-1206 (1994)). In Drosophila, the dendrite of the sensory neuron is enclosed in a cavity filled with a specialized receptor lymph, which is unusually rich in potassium ions, and is functionally equivalent to the potassium-rich endolymph of the vertebrate cochlea. These potassium ions produce a transepithelial potential difference, with the apical side of the epithelium being positively charged. Mechanical stimulation of the bristle, which is adjacent to the sensory neuron, generates a mechanoreceptor potential within the neuron, detectable as a negative deflection of the transepithelial potential, which reflects the flow of cations from the receptor lymph into the sensory neuron.
Activation of the hair cells of vertebrates also result in the influx of cations into cells (see, e.g., Hudspeth, Nature, 341:397-404 (1989)). Each hair cell has a number of specialized microvillar structures, called stereocilia, whose deflection results in the activation of a putative channel present on the surface of the cell. Interestingly, electrophysiological studies have suggested that these cells contain a similar number of receptor channels as they do stereocilia, suggesting that perhaps each receptor channel is coupled to a single stereocilium. In addition, studies of the kinetics of hair-cell activation have suggested that the putative mechanosensory receptors are directly stimulated by mechanical force, resulting in the direct opening of the channel without the involvement of second messengers.
Despite the great importance of mechanosensation for animal behavior and health, and the detailed electrophysiological understanding that has been gained from the above-described studies, almost nothing is known about the molecular basis of mechanosensory detection in eukaryotes. Several mutations and distantly related molecules involved in this process have, however, been found. In Drosophila, for example, a number of mutations have been isolated that disrupt mechanoreception, resulting in a variety of phenotypes such as reduced locomotor activity, total uncoordination, and even death (Kernan et al., Neuron 12:1195-1206 (1994)). Also, mutations have been identified in the nematode C. elegans that result in a loss of sensitivity to gentle touch (reviewed in Garcia-Aanoveros & Corey, Ann. Rev. Neurosci. 20:567-594 (1997)). In addition, a prokaryotic mechanosensory channel has been identified (Sukarev et al., Nature 368:265-268 (1994)). Still, despite these advances, the principle molecule of the mechanosensory transduction process in eukaryotes, the mechanically gated channel, has yet to be isolated or identified.
The identification and isolation of eukaryotic mechanosensory transduction channels would allow for the development of new methods of pharmacological and genetic modulation of mechanosensory transduction pathways. For example, availability of mechanosensory transduction channel proteins would permit screening for high-affinity agonists, antagonists, and modulators of mechanosensation in animals. Such molecules could then be used, e.g., in the pharmaceutical industry, to treat one or more of the many human conditions involving loss or hyperactivation of mechanosensation. In addition, the determination of nucleotide and amino acid sequences of mechanosensory transduction channels associated with a human condition would provide new tools for the diagnosis and/or treatment, e.g., gene-based treatment, of the condition.